Given the rarity of most single-gene Mendelian disorders, concerted efforts of data exchange between clinical and scientific communities are critical to optimize molecular diagnosis and novel disease ...gene discovery.
We designed and implemented protocols for the study of cases for which a plausible molecular diagnosis was not achieved in a clinical genomics diagnostic laboratory (i.e. unsolved clinical exomes). Such cases were recruited to a research laboratory for further analyses, in order to potentially: (1) accelerate novel disease gene discovery; (2) increase the molecular diagnostic yield of whole exome sequencing (WES); and (3) gain insight into the genetic mechanisms of disease. Pilot project data included 74 families, consisting mostly of parent-offspring trios. Analyses performed on a research basis employed both WES from additional family members and complementary bioinformatics approaches and protocols.
Analysis of all possible modes of Mendelian inheritance, focusing on both single nucleotide variants (SNV) and copy number variant (CNV) alleles, yielded a likely contributory variant in 36% (27/74) of cases. If one includes candidate genes with variants identified within a single family, a potential contributory variant was identified in a total of ~51% (38/74) of cases enrolled in this pilot study. The molecular diagnosis was achieved in 30/63 trios (47.6%). Besides this, the analysis workflow yielded evidence for pathogenic variants in disease-associated genes in 4/6 singleton cases (66.6%), 1/1 multiplex family involving three affected siblings, and 3/4 (75%) quartet families. Both the analytical pipeline and the collaborative efforts between the diagnostic and research laboratories provided insights that allowed recent disease gene discoveries (PURA, TANGO2, EMC1, GNB5, ATAD3A, and MIPEP) and increased the number of novel genes, defined in this study as genes identified in more than one family (DHX30 and EBF3).
An efficient genomics pipeline in which clinical sequencing in a diagnostic laboratory is followed by the detailed reanalysis of unsolved cases in a research environment, supplemented with WES data from additional family members, and subject to adjuvant bioinformatics analyses including relaxed variant filtering parameters in informatics pipelines, can enhance the molecular diagnostic yield and provide mechanistic insights into Mendelian disorders. Implementing these approaches requires collaborative clinical molecular diagnostic and research efforts.
To assess efficacy and toxicity of combination immunotherapy with ipilimumab plus nivolumab in routine practice in a retrospective multicentre cohort of patients with advanced melanoma.
This ...retrospective analysis included patients with advanced melanoma treated with ipilimumab and nivolumab between October 2015 and January 2020 at six centres in Australia, Europe and the United States of America. We describe efficacy outcomes (overall survival OS, progression-free survival PFS and objective response rate ORR) in treatment-naïve and pre-treated patients, with and without brain metastases, plus treatment-related adverse events (trAEs) in all patients treated.
A total of 697 patients were identified; 472 were treatment-naïve of which 138 (29.2%) had brain metastases, and 225 were previously treated of which 102 (45.3%) had brain metastases. At baseline, 32.3% had stage M1c and 34.4% stage M1d disease. Lactate dehydrogenase was high in 280 patients (40.2%). With a median follow-up of 25.9 months, median OS in the 334 treatment-naïve patients without brain metastases was 53.7 months (95% confidence interval CI 40.8-NR) and 38.7 months (95% CI 18.6-NR) for the 138 treatment-naïve patients with brain metastases. For the entire cohort the ORR was 48%, for treatment-naïve patients without brain metastases ORR was 56.6% with a median PFS of was 13.7 months (95% CI 9.6–26.5). Median PFS was 7.9 months (95% CI 5.8–10.4) and OS 38 months (95% CI 31-NR) for the entire cohort. Grade 3–4 trAE were reported in 44% of patients, and 4 (0.7%) treatment-related deaths (1 pneumonitis, 2 myocarditis and 1 colitis) were recorded.
The outcome and toxicity of combination immunotherapy with ipilimumab and nivolumab in a real-world patient population are similar to those reported in pivotal trials.
•Largest real-world cohort treated with combination immunotherapy for advanced melanoma.•Outcomes for real-world population are similar to registration trial.•Subgroup analyses offer helpful data to guide treatment decisions.
We previously identified mutations in Nardilysin (dNrd1) in a forward genetic screen designed to isolate genes whose loss causes neurodegeneration in Drosophila photoreceptor neurons. Here we show ...that NRD1 is localized to mitochondria, where it recruits mitochondrial chaperones and assists in the folding of α-ketoglutarate dehydrogenase (OGDH), a rate-limiting enzyme in the Krebs cycle. Loss of Nrd1 or Ogdh leads to an increase in α-ketoglutarate, a substrate for OGDH, which in turn leads to mTORC1 activation and a subsequent reduction in autophagy. Inhibition of mTOR activity by rapamycin or partially restoring autophagy delays neurodegeneration in dNrd1 mutant flies. In summary, this study reveals a novel role for NRD1 as a mitochondrial co-chaperone for OGDH and provides a mechanistic link between mitochondrial metabolic dysfunction, mTORC1 signaling, and impaired autophagy in neurodegeneration.
•NRD1 binds to and chaperones OGDH (α-KGDH) in mitochondria•Loss of NRD1 or OGDH leads to a progressive neurodegeneration•Loss of NRD1 or OGDH increases α-KG, elevates mTORC1 activity, and impairs autophagy•Rapamycin alleviates neuronal defects resulting from reduced NRD1 or OGDH function
Yoon et al. show that the proper folding of oxoglutarate dehydrogenase (OGDH), the Krebs cycle enzyme, requires Nardilysin (NRD1) in the mitochondria. Loss of Nrd1 or Ogdh causes an elevated level of α-ketoglutarate, which leads to neurodegeneration by promoting mTORC1 activity and reducing autophagy.
Biothreat detection has continued to gain attention. Samples suspected to fall into any of the CDC's biothreat categories require identification by processes that require specialized expertise and ...facilities. Recent developments in analytical instrumentation and machine learning algorithms offer rapid and accurate classification of Gram-positive and Gram-negative bacterial species. This is achieved by analyzing the negative ions generated from bacterial cell extracts with a modified linear quadrupole ion-trap mass spectrometer fitted with two-dimensional tandem mass spectrometry capabilities (2D MS/MS). The 2D MS/MS data domain of a bacterial cell extract is recorded within five s using a five-scan average after sample preparation by a simple extraction. Bacteria were classified at the species level by their lipid profiles using the random forest, k-nearest neighbor, and multilayer perceptron machine learning models. 2D MS/MS data can also be treated as image data for use with image recognition algorithms such as convolutional neural networks. The classification accuracy of all models tested was greater than 99%. Adding to previously published work on the 2D MS/MS analysis of bacterial growth and the profiling of sporulating bacteria, this study demonstrates the utility and information-rich nature of 2D MS/MS in the identification of bacterial pathogens at the species level when coupled with machine learning.
The Blue Button feature of online patient portals promotes patient engagement by allowing patients to easily download their personal health information. This study examines the adoption and use of ...the Blue Button feature in the Department of Veterans Affairs' (VA) personal health record portal, My HealtheVet.
An online survey presented to a 4% random sample of My HealtheVet users between March and May 2012. Questions were designed to determine characteristics associated with Blue Button use, perceived value of use, and how Veterans with non-VA providers use the Blue Button to share information with their non-VA providers.
Of the survey participants (N=18 398), 33% were current Blue Button users. The most highly endorsed benefit was that it helped patients understand their health history better because all the information was in one place (73%). Twenty-one percent of Blue Button users with a non-VA provider shared their VA health information, and 87% reported that the non-VA provider found the information somewhat or very helpful. Veterans' self-rated computer ability was the strongest factor contributing to both Blue Button use and to sharing information with non-VA providers. When comparing Blue Button users and non-users, barriers to adoption were low awareness of the feature and difficulty using the Blue Button.
This study contributes to the understanding of early Blue Button adoption and use of this feature for patient-initiated sharing of health information. Educational efforts are needed to raise awareness of the Blue Button and to address usability issues that hinder adoption.
With the approaching release of the DSM V in 2013, there has been much debate about the proposal to remove the diagnostic label of Asperger’s disorder from the new DSM. This study explored how health ...and education professionals perceive the conditions of autism and Asperger’s disorder and their views on the proposed diagnostic changes. Analysis of the 547 participant responses confirmed an increase stigma is associated with the label of autism, with autism considered to be a more severe than the condition of Asperger’s disorder. Approximately half of the participants reported being opposed to proposed diagnostic changes and of the remaining participants, 22 % supported the proposed changes and 28 % expressed uncertainty.
While polygenic risk scores (PRSs) enable early identification of genetic risk for chronic obstructive pulmonary disease (COPD), predictive performance is limited when the discovery and target ...populations are not well matched. Hypothesizing that the biological mechanisms of disease are shared across ancestry groups, we introduce a PrediXcan-derived polygenic transcriptome risk score (PTRS) to improve cross-ethnic portability of risk prediction. We constructed the PTRS using summary statistics from application of PrediXcan on large-scale GWASs of lung function (forced expiratory volume in 1 s FEV
and its ratio to forced vital capacity FEV
/FVC) in the UK Biobank. We examined prediction performance and cross-ethnic portability of PTRS through smoking-stratified analyses both on 29,381 multi-ethnic participants from TOPMed population/family-based cohorts and on 11,771 multi-ethnic participants from TOPMed COPD-enriched studies. Analyses were carried out for two dichotomous COPD traits (moderate-to-severe and severe COPD) and two quantitative lung function traits (FEV
and FEV
/FVC). While the proposed PTRS showed weaker associations with disease than PRS for European ancestry, the PTRS showed stronger association with COPD than PRS for African Americans (e.g., odds ratio OR = 1.24 95% confidence interval CI: 1.08-1.43 for PTRS versus 1.10 0.96-1.26 for PRS among heavy smokers with ≥ 40 pack-years of smoking) for moderate-to-severe COPD. Cross-ethnic portability of the PTRS was significantly higher than the PRS (paired t test p < 2.2 × 10
with portability gains ranging from 5% to 28%) for both dichotomous COPD traits and across all smoking strata. Our study demonstrates the value of PTRS for improved cross-ethnic portability compared to PRS in predicting COPD risk.
Concerns have been recognized about the operating characteristics of the standard 3 + 3 dose-escalation design. Various innovative phase 1 trial designs have been proposed to address the issues and ...new challenges posed by molecularly targeted agents. However, in spite of these proposals, the conventional design is still the most widely utilized.
A review of the literature of phase 1 trials and relevant statistical studies was performed.
Beyond statistical simulations, sparse clinical data exist to support or refute many of the shortcomings ascribed to the 3 + 3 rule method. Data from phase 1 trials demonstrate that traditional designs identified the correct dose and relevant toxicities with an acceptable level of precision in some instances; however, no single escalation method was proven superior in all circumstances.
Design selection should be guided by the principle of slow escalation in the face of toxicity and rapid dose increases in the setting of minimal or no adverse events. When the toxicity of a drug is uncertain or a narrow therapeutic window is suggested from preclinical testing, then a conservative 3 + 3 method is generally appropriate. However, if the therapeutic window is wide and the expected toxicity is low, then rapid escalation with a novel rule- or model-based design should be employed.
Human epidermal growth factor receptor 3 (HER3) is important in maintaining epidermal growth factor receptor-driven cancers and mediating resistance to targeted therapy. A phase I study of anti-HER3 ...monoclonal antibody LJM716 was conducted with the primary objective to identify the maximum tolerated dose (MTD) and/or recommended dose for expansion (RDE), and dosing schedule. Secondary objectives were to characterize safety/tolerability, pharmacokinetics, pharmacodynamics, and preliminary antitumor activity.
This open-label, dose-finding study comprised dose escalation, followed by expansion in patients with squamous cell carcinoma of the head and neck or esophagus, and HER2-overexpressing metastatic breast cancer or gastric cancer. During dose escalation, patients received LJM716 intravenous once weekly (QW) or every two weeks (Q2W), in 28-day cycles. An adaptive Bayesian logistic regression model was used to guide dose escalation and establish the RDE. Exploratory pharmacodynamic tumor studies evaluated modulation of HER3 signaling.
Patients received LJM716 3-40 mg/kg QW and 20 mg/kg Q2W (54 patients; 36 patients at 40 mg/kg QW). No dose-limiting toxicities (DLTs) were reported during dose-escalation. One patient experienced two DLTs (diarrhea, hypokalemia both grade 3) in the expansion phase. The RDE was 40 mg/kg QW, providing drug levels above the preclinical minimum effective concentration. One patient with gastric cancer had an unconfirmed partial response; 17/54 patients had stable disease, two lasting >30 weeks. Down-modulation of phospho-HER3 was observed in paired tumor samples.
LJM716 was well tolerated; the MTD was not reached, and the RDE was 40 mg/kg QW. Further development of LJM716 is ongoing.
Clinicaltrials.gov registry number NCT01598077 (registered on 4 May, 2012).
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